The goal of this project is to rapidly discover biomarkers for Parkinson's Disease (PD) by defining the spectrum of causal genetic loci for PD, not only for the purpose of accurate diagnosis and risk stratification but also in order to shed light on the underlying biology and pathways involved in PD pathogenesis for the purpose of future rational therapeutic development. There are 3 specific aims: 1. To perform array-based high-resolution oligonucleotide comparative genomic hybridization (aCGH) on 100 DNA samples from PD subjects for discovery of causal copy number variants (CNV). This will rely upon a subtractive methodology (PD cohort CNV frequency vs normal control CNV frequency to distinguish disease-specific genomic CNVs) utilizing external (publicly available) CNV databases in combination with an internal pre-existing database generated using a large number of normal individuals. 2. To validate significant PD-specific CNVs through the design of targeted assays (utilizing methods including exon specific MLPA and junction fragment PCR). 3. Having identified and validated PD-specific CNVs, to study in greater depth those that are the most promising (on the basis of frequency and genes implicated), by rapidly interrogating the total PD cohort (utilizing exon specific MLPA as well as next-generation sequencing, in order to cover any possible mutational mechanism), by comparison with a large number of normal control samples. PUBLIC HEALTH RELEVANCE: There is no doubt that the only rational approach to future therapeutic interventions in common disorders, such as Parkinson's Disease (PD), is one that will be based on a more precise knowledge of the underlying biological causes of such disorders. The successful application of genome wide copy number analysis for biomarker development in PD will facilitate improved diagnostic testing and risk stratification as well as yielding insight into the underlying pathogenesis of PD, paving the way for research into specific interventions, whether pharmaceutical or otherwise.